Effects of competitive and noncompetitive GABAA antagonists on the acquisition of a discrimination in squirrel monkeys

Abstract

There is evidence that low doses of convulsant agents may enhance acquisition under various behavioral procedures. The following experiments were undertaken to establish whether the putative GABA(A) antagonist pentylenetetrazole, and known GABA(A) receptor antagonists picrotoxin, picrotoxinin and bicuculine, might also enhance acquisition. Learning was studied under two different schedules of food presentation using the technique of repeated acquisition. Under this procedure, subject were required to acquire a different three-response sequence each session. Sequence completions were reinforced under a fixed-ratio five (FR 5) schedule, which engendered a low level of errors. A chain strained-ratio schedule was also studied because it engendered a high level of errors. Pentylenetetrazole (PTZ) (0.32-32mg/kg) generally produced a dose-related decrease in responding at higher doses (10-32mg/kg), while at lower doses (0.32-5.6mg/kg) response rate was not affected. PTZ generally disrupted accuracy of responding only at doses that decreased the rate of responding. Like PTZ, the noncompetitive GABA(A) receptor antagonist picrotoxin decreased the overall rate of responding and disrupted accuracy only at the higher doses tested (0.13-0.32mg/kg) in three of four subjects. At low doses (0.0032-0.1mg/kg), response rates and accuracy were unaffected when compared to the control ranges. Picrotoxinin, an active metabolite of picrotoxin, increased errors at doses that decreased the overall rate of responding. Conversely, the competitive GABA(A) receptor antagonist bicuculline (0.0032-0.56mg/kg) had no effect on accuracy and only decreased the rate of responding at doses that produced convulsions. Under the chain strained-ratio schedule, PTZ and picrotoxinin failed to enhance acquisition. These data suggest that pentylenetetrazole, picrotoxin, picrotoxinin and bicuculline do not reliably enhance acquisition in the squirrel monkey, and that differences exist between competitive and noncompetitive GABA(A) antagonists with regard to their effects on acquisition processes in the squirrel monkey. d-amphetamine, on the other hand, disrupted acquisition under the fixed-ratio schedule while at certain doses it enhanced acquisition under the strained-ratio schedule. The data also suggest that classical brain stem and cortical stimulants differ in terms of their ability to enhance acquisition under a strained-ratio schedule and that these differences may relate to their effects on conditioned reinforcement.